Researchers Develop a New Agent for Hemophilia A

Researchers have developed a new bypassing agent that mimics the pro-clotting activity of factor V Leiden and gives the clotting process more time to produce the clotting enzyme thrombin, according to preclinical research published in Blood. In their report, Stéphanie G.I. Polderdijk, of the Cambridge Institute for Medical Research at the University of Cambridge, and authors suggest that this treatment could someday help patients with hemophilia A and B – particularly those who develop inhibitors to standard clotting factor replacement therapies.

In the study, led by James A. Huntington, PhD, investigators attempted to reduce the activated protein C (APC) enzyme, which promotes bleeding, based on observations of patients with excessive factor V Leiden; in these patients, defects in the anticoagulant APC mechanism lead to an overactive production of the clotting enzyme thrombin.

“We hypothesized that if we targeted the protein C pathway, we could prolong thrombin production,” said Dr. Huntington, of the Cambridge Institute for Medical Research at the University of Cambridge.

The researchers administered these modified serine protease inhibitors, known as serpins, to mice with hemophilia B and then clipped their tails. This method led to decreased blood loss, which continued to decrease as the serpin dose increased. The highest dose reduced bleeding to the level of healthy mice. According to Dr. Huntington, “We engineered a serpin so that it could selectively prevent APC from shutting down thrombin production before the formation of a stable clot.”

Further injury models showed that serpin helped the majority of mice form stable clots, with higher doses resulting in quicker clot formation. The serpin also accelerated clot formation when added to blood samples from patients with hemophilia A.

“It is our understanding that because we are targeting a general anti-clotting process, our serpin could effectively treat patients with either hemophilia A or B, including those who develop inhibitors to more traditional therapy,” Dr. Huntington said.

The investigators hope to conduct human trials of subcutaneous serpin within three years.

Sources: Polderdijk SGI, Adams TE, Ivanciu L, et al. Design and characterization of an APC-specific serpin for the treatment of hemophilia. Blood. 2016 October 27. [Epub ahead of print]; American Society of Hematology press release, October 27, 2016.